Tacrine-xanomeline and tacrine-iperoxo hybrid ligands: Synthesis and biological evaluation at acetylcholinesterase and M1 muscarinic acetylcholine receptors

Maspero, Marco; Volpato, Daniela; Cirillo, Davide; Chen, Natalia Yuan; Messerer, Regina; Sotriffer, Christoph A.; Amici, Marco De; Holzgrabe, Ulrike; Dallanoce, Clelia

doi:10.1016/j.bioorg.2020.103633

Cited by 11 publications

(25 citation statements)

References 43 publications

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“…The conversion of aldehyde 7 into oxime 8, followed by the addition of cyanide should give hydroxylamine 9 [7]. The subsequent reduction to aminoacetonitrile 10 [8] followed by reaction with S 2 Cl 2 was expected to give the desired thiadiazole 5 [9]. We were interested in developing an independent synthesis for thiadiazole 5 to investigate its chemistry.…”

Section: Resultsmentioning

confidence: 99%

“…The conversion of aldehyde 7 into oxime 8 followed by the addition of cyanide should give hydroxylamine 9 [7]. The subsequen reduction to aminoacetonitrile 10 [8] followed by reaction with S2Cl2 was expected to give the desired thiadiazole 5 [9]. The reaction of quinazolinone-2-carbaldehyde 7 with hydroxylamine hydrochloride (1.1 equiv), in the presence of K2CO3 (1 equiv), in EtOH, at ca.…”

Section: Resultsmentioning

confidence: 99%

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(E)-4-Oxo-3,4-dihydroquinazoline-2-carbaldehyde Oxime

Kalogirou

Kourtellaris

Koutentis

2021

Molbank

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

(E)-4-Oxo-3,4-dihydroquinazoline-2-carbaldehyde Oxime

Kalogirou

Kourtellaris

Koutentis

2021

Molbank

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“…In 2020, Maspero et al reported THA hybrids 712 – 717 with xanomeline, a selective muscarinic acetylcholine receptor agonist and M1/M4 preferring muscarinic acetylcholine receptor activator [ 106 , 193 ]. Hybrids 712 – 717 were able to inhibit AChE; eight methylene units were optimal for the highest AChE inhibition.…”

Section: Tacrine Hybrids With Modulators Of Cholinergic/serotonergic ...mentioning

confidence: 99%

Tacrine-Based Hybrids: Past, Present, and Future

Bubley

Erofeev

Gorelkin

et al. 2023

IJMS

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Alzheimer’s disease (AD) is a neurodegenerative disorder which is characterized by β-amyloid (Aβ) aggregation, τ-hyperphosphorylation, and loss of cholinergic neurons. The other important hallmarks of AD are oxidative stress, metal dyshomeostasis, inflammation, and cell cycle dysregulation. Multiple therapeutic targets may be proposed for the development of anti-AD drugs, and the “one drug–multiple targets” strategy is of current interest. Tacrine (THA) was the first clinically approved cholinesterase (ChE) inhibitor, which was withdrawn due to high hepatotoxicity. However, its high potency in ChE inhibition, low molecular weight, and simple structure make THA a promising scaffold for developing multi-target agents. In this review, we summarized THA-based hybrids published from 2006 to 2022, thus providing an overview of strategies that have been used in drug design and approaches that have resulted in significant cognitive improvements and reduced hepatotoxicity.

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“…In the human brain, acetylcholine functions as a cholinergic neurotransmitter and plays an important role in cognition, learning, and memory. Over the past decades, many studies have found that a huge number of cholinergic neurons in the brains of AD patients are damaged, and the level of acetylcholine during nerve impulse transmission is greatly reduced, affecting signal transmission and leading to learning and cognitive failure [ 19 , 20 , 21 , 22 ]. Compelling evidence supports the concept that the shortage of acetylcholine is one of the main causes of AD, indicating that elevating acetylcholine level would improve AD patients [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Novel and Potent Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease from Natural (±)-7,8-Dihydroxy-3-methyl-isochroman-4-one

Jia

et al. 2022

Molecules

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Alzheimer’s disease (AD) is a neurodegenerative disease that causes memory and cognitive decline as well as behavioral problems. It is a progressive and well recognized complex disease; therefore, it is very urgent to develop novel and effective anti-AD drugs. In this study, a series of novel isochroman-4-one derivatives from natural (±)-7,8-dihydroxy-3-methyl-isochroman-4-one [(±)-XJP] were designed and synthesized, and their anti-AD potential was evaluated. Among them, compound 10a [(Z)-3-acetyl-1-benzyl-4-((6,7-dimethoxy-4-oxoisochroman-3-ylidene)methyl)pyridin-1-ium bromide] possessed potent anti-acetylcholinesterase (AChE) activity as well as modest antioxidant activity. Further molecular modeling and kinetic investigations revealed that compound 10a was a dual-binding inhibitor that binds to both catalytic anionic site (CAS) and peripheral anionic site (PAS) of the enzyme AChE. In addition, compound 10a exhibited low cytotoxicity and moderate anti-Aβ aggregation efficacy. Moreover, the in silico screening suggested that these compounds could pass across the blood–brain barrier with high penetration. These findings show that compound 10a was a promising lead from a natural product with potent AChE inhibitory activity and deserves to be further developed for the prevention and treatment of AD.

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Tacrine-xanomeline and tacrine-iperoxo hybrid ligands: Synthesis and biological evaluation at acetylcholinesterase and M1 muscarinic acetylcholine receptors

Cited by 11 publications

References 43 publications

(E)-4-Oxo-3,4-dihydroquinazoline-2-carbaldehyde Oxime

(E)-4-Oxo-3,4-dihydroquinazoline-2-carbaldehyde Oxime

Tacrine-Based Hybrids: Past, Present, and Future

Novel and Potent Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease from Natural (±)-7,8-Dihydroxy-3-methyl-isochroman-4-one

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